Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice International journal

Hayashi S.

Redox Biology Vol. 37 2020.10

アスベストとタルクは鉄過剰環境を形成し卵巣がんの発がんに関わる

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 Vol. 79回 page： OJ1 - 1 2020.10

Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium International journal

Ito F.

Redox Biology Vol. 36 2020.9

Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma International journal

Ohara Y.

Oncology Reports Vol. 44 ( 3 ) page： 838 - 848 2020.9

Role of carbonic anhydrases in ferroptosis-resistance International journal

Li Z.

Archives of Biochemistry and Biophysics Vol. 689 2020.8

Ferroptosis at the crossroads of infection, aging and cancer International journal

Toyokuni S.

Cancer Science Vol. 111 ( 8 ) page： 2665 - 2671 2020.8

Non-thermal plasma-activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism International journal

Ishikawa Kenji, Hosoi Yugo, Tanaka Hiromasa, Jiang Li, Toyokuni Shinya, Nakamura Kae, Kajiyama Hiroaki, Kikkawa Fumitaka, Mizuno Masaaki, Hori Masaru

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 688 2020.7

Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats International journal

Okazaki Y.

Cancer Science Vol. 111 ( 6 ) page： 2016 - 2027 2020.6

Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats. Reviewed International journal

Yasumasa Okazaki, Nobuaki Misawa, Shinya Akatsuka, Norihiko Kohyama, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

Cancer science Vol. 111 ( 4 ) page： 1180 - 1192 2020.4

Publishing type：Research paper (scientific journal)

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

DOI： 10.1111/cas.14358

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Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice Reviewed International journal

Funahashi S.

Free Radical Research Vol. 54 ( 2-3 ) page： 195 - 205 2020.3

アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣がんの発がんに関わる Reviewed International journal

本岡大社, 伊藤文哉, 豊國伸哉

日本病理学会会誌 Vol. 109 ( 1 ) page： 314 - 314 2020.3

Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway International journal

Yoshikawa Nobuhisa, Liu Wenting, Nakamura Kae, Yoshida Kosuke, Ikeda Yoshiki, Tanaka Hiromasa, Mizuno Masaaki, Toyokuni Shinya, Hori Masaru, Kikkawa Fumitaka, Kajiyama Hiroaki

SCIENTIFIC REPORTS Vol. 10 ( 1 ) 2020.1

Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions Reviewed International journal

Akatsuka S.

Free Radical Research 2020

Oxidative stress-dependent and -independent death of glioblastoma cells induced by non-thermal plasma-exposed solutions Reviewed International journal

Tanaka Hiromasa, Mizuno Masaaki, Katsumata Yuko, Ishikawa Kenji, Kondo Hiroki, Hashizume Hiroshi, Okazaki Yasumasa, Toyokuni Shinya, Nakamura Kae, Yoshikawa Nobuhisa, Kajiyama Hiroaki, Kikkawa Fumitaka, Hori Masaru

SCIENTIFIC REPORTS Vol. 9 ( 1 ) page： 13657 2019.9

How iron is handled in the course of heme catabolism: Integration of heme oxygenase with intracellular iron transport mechanisms mediated by poly (rC)-binding protein-2. International journal

Yanatori I, Richardson DR, Toyokuni S, Kishi F

Archives of biochemistry and biophysics Vol. 672 page： 108071 2019.9

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia. Reviewed International journal

Zan Li, Li Jiang, Shan Hwu Chew, Tasuku Hirayama, Yoshitaka Sekido, Shinya Toyokuni

Redox biology Vol. 26 page： 101297 - 101297 2019.9

Language：English Publishing type：Research paper (scientific journal)

Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2- and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells.

DOI： 10.1016/j.redox.2019.101297

アスベストは鉄過剰環境を形成し卵巣癌の発癌に関わる(Asbestos contributes to ovarian carcinogenesis via iron overload) Reviewed International journal

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 Vol. 78回 page： E - 1077 2019.9

l-Dehydroascorbic acid recycled by thiols efficiently scavenges non-thermal plasma-induced hydroxyl radicals Reviewed International journal

Yasumasa Okazaki, Hiromasa Tanaka, Masaru Hori, Shinya Toyokuni

Archives of Biochemistry and Biophysics Vol. 669 page： 87 - 95 2019.7

アスベストの曝露は上皮性悪性卵巣腫瘍の発癌に関与する Reviewed International journal

水野勇太, 本岡大社, 豊國伸哉

日本病理学会会誌 Vol. 108 ( 1 ) page： 460 - 461 2019.4

A scrutiny of circulating microRNA biomarkers for drug-induced tubular and glomerular injury in rats.

Toxicology Vol. 415 page： 26-36 2019.3

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Papers - TOYOKUNI Shinya